Tang-Nai-Kang Alleviates Pre-diabetes and Metabolic Disorders and Induces a Gene Expression Switch toward Fatty Acid Oxidation in SHR.Cg-Leprcp/NDmcr Rats

ABSTRACT Estrogen-related receptors (ERRs) are orphan nuclear receptors activated by the transcriptional coactivator peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α (PGC-1α), a critical regulator of cellular energy metabolism. However, metabolic target genes downstream of ERRα have not been well defined. To identify ERRα-regulated pathways in tissues with high energy demand such as the heart, gene expression profiling was performed with primary neonatal cardiac myocytes overexpressing ERRα. ERRα upregulated a subset of PGC-1α target genes involved in multiple energy production pathways, including cellular fatty acid transport, mitochondrial and peroxisomal fatty acid oxidation, and mitochondrial respiration. These results were validated by independent analyses in cardiac myocytes, C2C12 myotubes, and cardiac and skeletal muscle of ERRα−/− mice. Consistent with the gene expression results, ERRα increased myocyte lipid accumulation and fatty acid oxidation rates. Many of the genes regulated by ERRα are known targets for the nuclear receptor PPARα, and therefore, the interaction between these regulatory pathways was explored. ERRα activated PPARα gene expression via direct binding of ERRα to the PPARα gene promoter. Furthermore, in fibroblasts null for PPARα and ERRα, the ability of ERRα to activate several PPARα targets and to increase cellular fatty acid oxidation rates was abolished. PGC-1α was also shown to activate ERRα gene expression. We conclude that ERRα serves as a critical nodal point in the regulatory circuitry downstream of PGC-1α to direct the transcription of genes involved in mitochondrial energy-producing pathways in cardiac and skeletal muscle.

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Sexually Dimorphic Responses to a High-Refined Carbohydrate Diet in a Nonalcoholic Fatty Liver Disease Mouse Model

Current Developments in Nutrition ◽

10.1093/cdn/nzaa040_016 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 16-16

Author(s):

Michael Daniels ◽

Chun Liu ◽

Kang-Quan Hu ◽

Xiang-Dong Wang

Keyword(s):

Gene Expression ◽

Fatty Acid ◽

Hepatic Steatosis ◽

Fatty Acid Oxidation ◽

Acid Oxidation ◽

Sexually Dimorphic ◽

Male Mice ◽

Carbohydrate Diet ◽

Nonalcoholic Fatty Liver ◽

Female Mice

Abstract Objectives Nonalcoholic fatty liver disease (NAFLD) incidence and prevalence have been reported to be higher in men than women, however, the effects of sexual dimorphism on NAFLD risk and progression have not been adequately examined. Our lab has previously shown that a liquid high-refined carbohydrate diet (HRCD) induced more severe hepatic steatosis compared to an isocaloric high fat diet in male mice. Also, HRCD-induced reduction in sirtuin 1 (SIRT1), an NAD-dependent deacetylase protein, has previously been implicated in NAFLD pathogenesis. Therefore, we investigated whether there were sexually dimorphic responses to a liquid high-refined carbohydrate diet (HRCD) in male and female, wildtype and SIRT1-deficient mice. Methods Male and female 10–12-week-old wildtype (SIRT1 +/+: n = 12; M = 6, F = 6) and mice carrying a heterozygous H355Y SIRT1 point mutation (SIRT1 +/y: n = 14; M = 7, F = 7) were both fed a HRCD (Lieber-DeCarli liquid diet supplemented with maltose dextrin; 47% energy from refined carbohydrate, Dyets, #710,260) for 5 weeks and 9 weeks. Hepatic gene expression was examined using qRT-PCR. Plasma ALT (alanine transaminase) and hepatic MDA (malondialdehyde) levels were determined using colorimetric assay kits. Hepatic steatosis scoring was conducted by analyzing Hematoxylin and Eosin (H&E) stains. Results 9 weeks of HRCD induced significantly less hepatic steatosis in female mice irrespective of genotype compared to male mice as determined by grading of H&E stains (P < 0.05). Furthermore, liver expression of several fatty acid oxidation genes (CPT1, ACOX1) was significantly higher in females (P < 0.05), which potentially suggests increased fatty acid oxidation. Additionally, female mice had significantly increased antioxidant gene expression (GPX4, SOD1, SOD2, Catalase) and significantly lower hepatic MDA (P < 0.05), which indicate an increased capacity to mitigate oxidative stress. Lastly, plasma ALT levels were significantly lower in females compared to males after 9 weeks of HRCD (P < 0.05). Conclusions Collectively, these data indicate that female mice are moderately protected against HRCD-induced NAFLD compared to male mice, potentially through increased hepatic fatty acid oxidation and superior mitigation of oxidative stress due to increased antioxidant system gene expression in the liver. Funding Sources HNRCA, USDA/ARS Grants.

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Reduced hepatic fatty acid oxidation in fasting PPARα null mice is due to impaired mitochondrial hydroxymethylglutaryl-CoA synthase gene expression

FEBS Letters ◽

10.1016/s0014-5793(00)01648-3 ◽

2000 ◽

Vol 475 (3) ◽

pp. 163-166 ◽

Cited By ~ 62

Author(s):

Cédric Le May ◽

Thierry Pineau ◽

Karine Bigot ◽

Claude Kohl ◽

Jean Girard ◽

...

Keyword(s):

Gene Expression ◽

Fatty Acid ◽

Fatty Acid Oxidation ◽

Acid Oxidation ◽

Hepatic Fatty Acid ◽

Hepatic Fatty Acid Oxidation

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The role of chicken ovalbumin upstream promoter transcription factor II in the regulation of hepatic fatty acid oxidation and gluconeogenesis in newborn mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00433.2014 ◽

2015 ◽

Vol 308 (10) ◽

pp. E868-E878 ◽

Cited By ~ 4

Author(s):

Julien Planchais ◽

Marie Boutant ◽

Véronique Fauveau ◽

Lou Dan Qing ◽

Lina Sabra-Makke ◽

...

Keyword(s):

Gene Expression ◽

Transcription Factor ◽

Fatty Acid ◽

Fatty Acid Oxidation ◽

Acid Oxidation ◽

Newborn Mice ◽

Factor Ii ◽

Upstream Promoter ◽

Cpt I ◽

Chicken Ovalbumin

Chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) is an orphan nuclear receptor involved in the control of numerous functions in various organs (organogenesis, differentiation, metabolic homeostasis, etc.). The aim of the present work was to characterize the regulation and contribution of COUP-TFII in the control of hepatic fatty acid and glucose metabolisms in newborn mice. Our data show that postnatal increase in COUP-TFII mRNA levels is enhanced by glucagon (via cAMP) and PPARα. To characterize COUP-TFII function in the liver of suckling mice, we used a functional (dominant negative form; COUP-TFII-DN) and a genetic (shRNA) approach. Adenoviral COUP-TFII-DN injection induces a profound hypoglycemia due to the inhibition of gluconeogenesis and fatty acid oxidation secondarily to reduced PEPCK, Gl-6-Pase, CPT I, and mHMG-CoA synthase gene expression. Using the crossover plot technique, we show that gluconeogenesis is inhibited at two different levels: 1) pyruvate carboxylation and 2) trioses phosphate synthesis. This could result from a decreased availability in fatty acid oxidation arising cofactors such as acetyl-CoA and reduced equivalents. Similar results are observed using the shRNA approach. Indeed, when fatty acid oxidation is rescued in response to Wy-14643-induced PPARα target genes (CPT I and mHMG-CoA synthase), blood glucose is normalized in COUP-TFII-DN mice. In conclusion, this work demonstrates that postnatal increase in hepatic COUP-TFII gene expression is involved in the regulation of liver fatty acid oxidation, which in turn sustains an active hepatic gluconeogenesis that is essential to maintain an appropriate blood glucose level required for newborn mice survival.

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